Absolute Quantification of Residual Solvent in Mesoporous Silica Drug Formulations Using Magic-Angle Spinning NMR Spectroscopy

Abstract

Porous silica is used as a drug delivery agent to improve the bioavailability of sparsely soluble compounds. In this approach, the active pharmaceutical ingredient (API) is commonly loaded into the porous silica by incipient wetness impregnation using organic solvents. Subsequent solvent elimination is critical as the residual solvent concentration cannot exceed threshold values set by health and safety regulations (e.g., EMA/CHMP/ICH/82260/2006). For dichloromethane and methanol, for example, residual concentrations must be below 600 and 3000 ppm, respectively. Today, EU and USA Pharmacopoeias recommend tedious procedures for residual solvent quantification, requiring extraction of the solvent and subsequent quantification using capillary gas chromatography with static headspace sampling (sHS-GC). This work presents a new method based on the combination of standard addition and absolute quantification using magic-angle spinning nuclear magnetic resonance spectroscopy (MAS qNMR). The methodology was originally developed for absolute quantification of water in zeolites and has now been validated for quantification of residual solvent in drug formations using mesoporous silica loaded with ibuprofen dissolved in DCM and MeOH as test samples. Interestingly, formulations prepared using as-received or predried mesoporous silica contained 5465 versus 484.9 ppm DCM, respectively. This implies that the initial water content of the silica carrier can impact the residual solvent concentration in drug-loaded materials. This observation could provide new options to minimize the occurrence of these undesired solvents in the final formulation.

Illuminating the Black Box: A Perspective on Zeolite Crystallization in Inorganic Media

“…With its high sensitivity and short measurement times, liquid-state 27 Al NMR is ideally suited to monitor the evolution of aluminosilicate during crystallization . Static and MAS NMR measurements are possible at temperatures of up to 90 °C and can be performed in a quantitative way, − thus enabling in situ studies. Also here, homogeneous synthesis media such as HSILs excel for this purpose due to their relatively simple physiochemical nature.…”

Noncontact In Situ Multidiagnostic NMR/Dielectric Spectroscopy

“…Since the degree of reorganization of the water network is dependent on the surface chemistry, determination of the change in dielectric properties of the intruded water offers a versatile methodology to characterize the influence of specific surface chemistry. This, in combination with the possibility of simultaneous access to quantitative atomic-level information about speciation, interactions, dynamics, etc., from the NMR spectra, ,, makes the developed methodology a versatile surface characterization technique for characterizing and generating structure–function relationships for a wide variety of porous materials like zeolites, periodic mesoporous silicas, organo silicas, etc., with applications ranging from catalysis, adsorption, and energy storage.…”

“…Not only is NMR characterization nearly unaffected by the length scale of periodicity, with the advent of high-pressure magic-angle spinning (MAS), , but also high-pressure in situ MAS NMR studies of nanoconfined water systems are within reach. NMR probes local chemical composition and provides molecular-level information on molecular dynamics and intermolecular interactions, including those of and with the confining host material. ,− It yields absolute quantification ( 1 H, 2 H, 13 C, 29 Si, 17 O,···) and probes the local chemical environment of H 2 and H 2 O molecules and their deuterated forms. − While NMR is focused on local atomic-level characterization, dielectric relaxation spectroscopy (DRS), the time-domain variant of electrochemical impedance spectroscopy (EIS), yields medium-to-long-range information on the confined water phase and its phase transitions . For water confined in hydrophobic mesoporous (organo-)­silicas, for example, DRS revealed a nonfreezable water layer at the pore wall/water interface, demonstrating layering of the confined water .…”

Hydrogen bonding to oxygen in siloxane bonds drives liquid phase adsorption of primary alcohols in high-silica zeolites

“…For investigating alcohol and water adsorption, nuclear magnetic resonance spectroscopy (NMR) is one of the preferred techniques, as it enables absolute quantification while simultaneously providing insight in the molecular organization of the adsorbate inside the zeolite pores and its interactions with the pore wall. [54][55][56] This manuscript reports on the liquid phase adsorption of C 1 -C 5 alcohols on ZSM-5 zeolites with Si/Al ratio in the range of 11.5-140. The crystallinity and microporosity of the different zeolites were ensured by PXRD 57 (Fig.…”

“…For investigating alcohol and water adsorption, nuclear magnetic resonance spectroscopy (NMR) is one of the preferred techniques, as it enables absolute quantification while simultaneously providing insight in the molecular organization of the adsorbate inside the zeolite pores and its interactions with the pore wall. 54–56…”